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Improved pulmonary function test (PFT) after 1 one year of Sublingual

Immunotherapy (SLIT) in unison with pharmacotherapy in mild allergic
asthmatics

Article  in  Immunology Letters · December 2020

DOI: 10.1016/j.imlet.2020.12.004

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 Immunology Letters 230 (2021) 36–41

Contents lists available at ScienceDirect

Immunology Letters
journal homepage: www.elsevier.com/locate/immlet

Improved pulmonary function test (PFT) after 1 one year of Sublingual

Immunotherapy (SLIT) in unison with pharmacotherapy in mild
allergic asthmatics
Afaq H. Beigh a, Roohi Rasool a, *, Fizalah Kawoosa a, Sharika manzoor a, Rabiya Rashid a,
Khurshid Iqbal Andrabi b, Zafar A. shah a, Taha Qureshi a
a
Allergy Clinic, Department of Immunology, and Molecular Medicine, Sher I Kashmir Institute of Medical Sciences Srinagar Kashmir, India
b
Department of Biotechnology, University of Kashmir Srinagar Kashmir, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Allergen immunotherapy (AIT) is a promising treatment for allergic disease that induces immuno­
Allergic asthma logical tolerance through the administration of specific allergens. The study of AIT is in its early stage and its
Allergen Specific Immunotherapy clinical effects are not well elucidated. The present study was aimed at determining the effect of AIT on pul­
FEV1
monary function and serum variables of mild allergic asthma patients.
FEV1/FVC
Methods: A total of 80 patients with mild allergic asthma were recruited for the study. Allergen Specific
Total IgE
Inhaled corticosteroids Immunotherapy was administered in the form of Sublingual Immunotherapy and consisted of a build up phase
followed by a maintenance phase (six months each respectively). Total serum IgE and vitamin D levels were
quantified by ELISA. The percent eosinophill count was determined by cell analyzers. Pulmonary function test
was performed at the baseline and after the end of study period. Subjective symptom score was recorded in the
form of asthma control questionnaire score.
Results: There was a significant increase in the pre FEV1% and pre FEV1/FVC post AIT administration. A sig­
nificant decrease in the total serum IgE was found post AIT. A decrease in Asthma control Questionnaire (ACQ)
scores indicated an improvement in clinical symptoms. Besides there was a significant effect on ICS discontin­
uation after AIT.
Conclusion: The study supports SLIT as an effective treatment for Immunomodulation in mild allergic asthmatics
besides it gives us significant information regarding the safety and efficacy of SLIT in such patients.

1. Introduction
The etiology of allergic asthma can be multifactorial. [1] It is
considered to be a blend of genetic and environmental factors [2].
Principally all types of asthma are an exaggerated hypersensitive re­
sponses which is are described as an IgE-mediated response [3]. Theses
responses are triggered by an offending agent, whether it be an allergen
or environmental agent (such as air pollutant) resulting in an increased
presence of eosinophils, lymphocytes and mast cells. This causes airway
inflammation and damage to the bronchial epithelium. [4–6]Approxi­
mately, 300 million people throughout the world are affected by asthma
[7]. Like other atopic conditions, the T Helper -2 (Th-2) immune
response is predominant in asthma. The enhanced production of IgE and
eosinophilic inflammation as well as increase in the levels of IL-4,IL-5,
IL-9 & IL-13 in the airways is caused by heightened levels of Th-2
cells. [8]. There are several endotypes of asthma, among which the
allergic asthma is the most common form caused by exposure to the
substances that tigger allergy symptoms. The most important compo­
nent of its treatment therapy includes allergen avoidance which is
practically impossible. As a result, pharmacotherapy especially anti­
histamines, corticosteroids & bronchodilators has been the mainstay of
management in the allergic diseases [9]. It suppresses inflammation but
provides temporary relieve from symptoms. However, allergen specific
immunotherapy (allergen AIT) is the only way of treatment which can
change the disease course, provide a long term cure additionally
reducing the need for symptomatic and anti-inflammatory medication.
The allergen SIT is based on the principle that by administration of
repeated increased doses of allergen, immunological tolerance is

* Corresponding author.
E-mail address: Roohi_wani@yahoo.com (R. Rasool).

https://doi.org/10.1016/j.imlet.2020.12.004
Received 3 September 2020; Received in revised form 9 December 2020; Accepted 11 December 2020
Available online 16 December 2020
0165-2478/© 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
A.H. Beigh et al. Immunology Letters 230 (2021) 36–41

developed against that particular allergen via multiple cellular and

molecular mechanisms [10]. It shifts Th2 cell response to Th1 response,
also reduces number of inflammatory cells with their mediators in the
airways & nasal mucosa and induces regulatory cells to release IL-10 &
TGF-β which in turn enhances synthesis of IgG1, IgG4 & IgA and sup­
press IgE production. [11]. Moreover, the sensitization to new allergen
& progression of disease is also prevented by it. The persistence of
improvement both in clinical & immunological parameters after cessa­
tion of treatment indicates effectiveness of allergen SIT [9]. Subjective
Symptom score is an important indicator for accessing the clinical and
symptomatic improvement in patients [12,13]. Since allergen SIT can
diminish airway inflammation, it can improve lung functioning in
asthmatic patients [9]. The mechanism by which AIT modulates the
pulmonary function variables remains a topic of research in Allergology
[14]. Our study, being one of its first kind from India, is aimed at
determining the efficacy of allergen specific immunotherapy (allergen
AIT) particularly SLIT and its impact on improving lung functioning,
total serum IgE and asthma control questionnaire score (Figs. 1–3). Fig. 2. Change in FEV1/FVC before and after AI.

2. Material methods

2.1. Patients

A total 80 patients with perennial allergic asthma from Sher-I-

Kashmir Institute of Medical Sciences were recruited into this study.
The demographic data of the patients is presented in Table 1. All the
allergic asthmatics were from the mild allergic asthma category as their
pre FEV1% range was ≥ 80 %. The diagnosis of allergic asthma was
based on clinical history and positive skin prick test. Exclusion criteria
included the presence of acute or chronic infectious disorders, autoim­
mune diseases, malignancies or other inflammatory disorders that are
contraindications to specific immunotherapy (SIT). The study was
approved by the institutional ethics committee of Sher-I-Kashmir Insti­
tute of Medical sciences. All the methods were carried out in accordance
with the approved guidelines. Written informed consent was obtained Fig. 3. Rate of ICS discontuation.
from all participants.
Severity of airflow obstruction based on percentage (%) predicted
forced expiratory volume in 1 s (FEV1). Table 1
Types of Allergens used for Skin Prick Test (SPT).
FEV1 % predicted Stage
>80 % Mild S.no Name Of Allergen S.No Name Of Allergen
50− 75% Moderate
01 D-farinae 26 Alder(Elnus glutinosa)
30− 49% Severe
02 D-Pteronyssinus 27 Dandelion
<30 % Very severe
03 Blomia sp 28 Short Ragweed
04 Aspergillus Fumigates 29 Rye Grass
05 Aspergillus Niger 30 Cenchrus Barbatus
06 Alternaria alternata 31 Locust black
2.2. Skin prick test (SPT) 07 Cyanadon dactylon 32 Nettle
08 Cyperus Rotundus 33 Engl Plantain
09 Parthenium hysterophorus 34 Meadow Fescue
SPT was performed in all subjects with the following allergen 10 Acacia arabica 35 Maple
11 Amaranthus spinosus 36 Velvet Grass
12 Chenopodium alba 37 House Dust
13 Xanthium strumeriun 38 Saw Dust
14 Brassica nigra 39 Grain Dust (rice)
15 Eucalyptus sp 40 Grain Dust (Wheat)
16 Ricinus communis 41 Hay Dust
17 Zea mays 42 Cat Epithelia
18 Prosopis juliflora (kikar) 43 Dog Epithelia
19 Pythaangustata 44 Chicken Epithelia
20 Cannabis sativa 45 Sheep Wool
21 Hazel 46 Cockroach
22 Birch (Betula alba) 47 Honey Bee
23 Mugwort (Artemesia vulgaris) 48 Red Ant
24 Poplar(Populus alba) 49 Mosquito
25 Kentucky blue grass 50 Wasp

extracts (Allergopharama, Germany): D. pteronyssinus, D. farinae, grass

pollen mix, cat and dog dander, American cockroach, mould mix, tree
pollen mix and weed pollens. The list of Allergens used for SPT is listed
Fig. 1. Change In FEV1/FVC before and after AIT.

37
A.H. Beigh et al. Immunology Letters 230 (2021) 36–41

in Table 2. The mean of the largest diameter of the wheal was recorded
as the response to the SPT. Histamine (0.01 mg/mL) was used as a
positive control and saline was used as a negative control.
2.3. Blood sample collection and serum separation
Peripheral blood samples were collected from each subject (5 mL/
person/time) via vein puncture. The serum was separated from the
whole blood by centrifugation and was stored at − 80 ◦ C till further use.
2.6. Determination of total IgE, Vitamin-D levels and Eosinophill% count
The serum levels of total IgE and Vitamin-D were quantified by ELISA
with reagent kits (Boster Bio-Tech) following the manufacturer’s infor­
mation. Eosinophill% count was determined by Beckman Coulter
analyzer.
2.7. Asthma control questionnaire (ACQ) and inhaled corticosteroid
discontuation

2.4. Spirometry
The severity of asthma was determined by Allergy control Ques­
tionnaire which is a simple questionnaire to measure the adequacy of
Lung function was assessed by spirometry (Medikro®, Kuopio,
asthma control and change in asthma control which occurs either
Finland) following standard protocol according to Knudson et al. [15,
spontaneously or as a result of treatment. In general a score below 1.0 is
16] The patients used nose clips and were coached through standard
controlled asthma, above 1 is not well controlled and between 0.75 and
forced expiratory manoeuvres. Patients in standing position were asked
1.25 is on the border line.
to take a breath as deep as possible and blow as quick and hard as she/he
can into the mouthpiece. The best of three successful manoeuvres was
recorded and expressed as the percentage of predicted values for gender, 2.8. Quantification of serum specific HDM IgE
age and height as forced expiratory volume in 1 s (FEV1), forced vital
capacity (FVC), forced mid-expiratory flow rate (FEF25– 75 %) and peak Serum HDM-specific IgE levels were determined by using the
expiratory flow rate (PEF). Normal lung function test reference values of ImmunoFluoriMetric assay procedure (ImmunoCAP, Thermo Fisher
Polgar and Promadhat were used to generate the predicted values . Scientific, CA, USA) before AIT and after one year of AIT. Quantitative-
specific IgE concentrations were expressed in kU/l according to the
2.5. Allergen specific immunotherapy AIT traceable calibration to the second Implementation Research Project
WHO for Human IgE. sIgE levels were considered positive if they were
A total of 96 patients were initially included in the study. The over 0.35 kU/l.
Allergen specific immunotherapy/Sublingual Immunotherapy (SLIT)
lasted for about one year consisting of build up dose and maintainance
dose. The Allergoid formation was provided by (BAC) Bangalore allergy 2.9. Statistical analysis
centre customised for each patient. As all of the patients in our study
were sensitive to either HDM Dp or HDM Df or both, so the formulation Statistical analysis was performed using SPSS 25.0 package (SPSS
of SLIT tablet was according to the sensitivity but the duration and Inc, Chicago, IL). Data were expressed as mean ± S.D. Wilcoxon Rank
dosage was the same. The SIT was initiated as a treatment dose at a sign Test, Mann Whitney U test and paired T-test were carried out be­
dosage of 20 U, and was continued weekly with an increase in the dosage tween the variables studied. Significance was defined for P-value < 0.05.
each week; the dosages were 20, 40, 80, 200, 400, 800, 2,000, 4,000,
8,000, 10,000, 20,000, 40,000, 60,000, 80,000 and 100,000 U, 3. Results
respectively. The maintenance dose was 100,000 U once a week until the
end of the one year. The VitD3 was prescribed by physicians; the pa­ 3.1. Patient characteristics
tients took one capsule (2000 IU) weekly. Among total of ninety six 96
patients sixteen (16) patients were lost up during the period of study due We enrolled 80 allergic asthma patients for the study, who were
to non compliance with study protocol hence were excluded from the monosensitized to only House dust Mite allergens namely Dermato­
study cohort. phagoides farinae (Df) and Dermatophagoides Pteronyssinus (Dp). All
the patients received Allergen specific Immunotherapy via sublingual
Table 2 route in the form of Sublingual Immunotherapy tablets (SLIT tablets)
Baseline characteristics and demography. according to standard protocol. Out of total 80 patients, 66 were females
and 14 were males. Out of 80 patients, 44 were from urban and 36 were
Parameters Pre AIT μ ± S.D Post AIT μ ± S.D P-value
n = 80 n = 80 from rural areas. During the course of Allergen specific immunotherapy
treatment, mild allergic group of patients were on ICS reaching a mean
Rural 36 do
Urban 44 do
dose of 320 ± 92.30 ug/day. These patients were followed up in order to
Males 14/80 14/80 determine the effect of AIT on pulmonary function variables and serum
Females 66/80 66/80 parameters.
*ICS dosage ug/day 320 ± 92.30 220 ± 87.23 0.001
Monosentizied 80/80
Severity of Asthma 3.2. Baseline spirometry
Mild 80
Severe 0
polysensitized 00/80 We assessed the base line pulmonary function test in order to assess
Duration Of AIT One year the initial pulmonary function parameters prior to allergen specific
SLIT 80/80 immunotherapy. We also used PFT as the basis for setting up the pre­
SLIT, sublingual immunotherapy. *Paired T test. requisite of patients for Allergen Immunotherapy; only those patients
with pre% FEV1 > 70 % were enrolled for AIT. The patients were
classified as mild, moderate and severe according to the pre% FEV1,
clinical history, symptoms and recent exacerbations status following
ATS/ERTS guidelines [17]We didn’t stratify the patients into mild and
moderate group because the size was low in case of moderate asthmatics
and hence the group analysis could yield biased results.

38
A.H. Beigh et al. Immunology Letters 230 (2021) 36–41

3.3. Forced expiratory volume in 1 s FEV1 Table 4

Change in clinical parameters before and after AIT.
The Pre % FEV1 was 81.97 ± 17.8 prior to Allergen Specific Parameters Pre AIT ± S.D Post AIT ± S.D P-Value
Immunotherapy, which increased to 87.76 ± 12.22 % after one year of
Vitamin D ng/mL 18.34 ± 10.23 26.34 ± 9.24 0.001
AIT. Although there was slight increase in the FEV1 the change was still IgE KIU/mL 798 ± 89 610 ± 95 0.002
statistically significant Table 3 Fig 1(P = 0.04). Eosinophills% 2.2 ± 0.23 1.8 ± 0.12 0.06

Paired T test.
3.4. FEV1/FVC or Tiffeneaupli-Index

The FEV1/FVC % was 81.97 ± 17.8 before the start of Allergen Table 7
Specific Immunotherapy which increased to 88.89 ± 12.70 % after one Effect of AIT on the Serum levels of specific HDM IgE.
year of AIT. The increase difference in the FEV1/FVC% was statistically Parameters Pre AIT n=80 Post AIT n=80 P-value
significant (P = 0.02). Although we find a slight increase in the FVC% in
ss IgE HDM Dp 86.54±34.87 67.32±39.25 0.09
our group of patients that underwent AIT but the statistical significance ss IgE HDM Df 97.65±40.65 105.65±83.12 0.10
was not achieved Table 3 Fig 2(P > 0.05). ss IgE HDM Dp/Total IgE 0.10 0.11 0.07
ss IgE HDM Df/ Total IgE 0.12 0.17 0.08
3.5. Total IgE and Vitamin D levels Paired t-test.

The levels of total serum IgE were very high (798 ± 89 IU/mL) at the
pre immunotherapy stage. The introduction of AIT resulted in the Table 5
reduction of total IgE to 610 ± 95 IU/mL. Though still high, there was Subjective Symptom Score before and After AIT.
significant decrease in the total serum IgE (P = 0.001).The patients were Parameter Pre AIT ± S.D Post AIT ± S.D P-Value
initially deficient in Vitamin D having mean levels of 18.34 ± 10.23 ng/
Allergy Control Questionnaire 2.49 ± 0.21 1.06 ± 0.11 0.001
mL, but after AIT the levels increased to 26.34 ± 9.24 ng/mL and the
increase was found to be statistically significant Table 4(P = 0.001). Mann Whitney Test.

3.6. Transition in serum HDM specific IgE levels before and after AIT
Table 6
Rate of Inhaler Discontuation.
we found that before the administration of AIT the levels of Serum
Inhaler Intake per day Pre AIT n = 80 Post AIT n = 80
Specific HDM to Dp and Df allergens were low which increased after one
year of AIT but the increase was not stastically significant Table 7. The Zero 42 59
01 35 21
levels of Dp IgE were low as compared to the levels of Df Specific IgE.
02 03 00
The serum specific to IgE total IgE ratio was also low in case of HDM Dp
as compared to HDM Df Table 7. The ratio difference was not stastically
significant. were poly sensitive according to their skin prick test. The allergen
avoidance measures and pharmacotherapy are the main stay treatment
3.7. Allergy control questionnaire in allergic asthma, however many patients continue to have disease
symptoms and an impaired quality of life. Besides, pharmacotherapy has
The subjective symptom score of our group were statistically sig­ its own benefit to risk ratio. [18] Allergen immunotherapy (AIT) is
nificant (P < 0.05). The pre AIT ACQ score was 2.49 ± 0.21 whereas the currently the best available treatment that targets the underlying
post AIT ACQ score decreased to 1.06 ± 0.11 indicating the effectiveness pathophisyology of the allergic disease that has a disease modifying
of AIT in ameliorating subjective symptoms associated with allergic effect and is a recommended treatment regime by Global Imitative for
asthma Table 5. Asthma (GINA) 2019 gudielines [19,20]Allergen Immunotherapy has an
immunomodulatory effect in terms of shifting the Th2 balance to T-reg,
3.8. Rate of inhaled corticosteroid (ICS) discontinuation induction of IL-10 iT-reg and B-reg cells and generation of blocking
antibodies and secretion of IL-10 and TGF-β1 [4,5,23–25]. The immu­
Our patients were put on ICS having mean levels of 310 ± 75.30 ug/ nomodulatory effect of allergen specific immunotherapy goes far
mL during pre immunotherapy stage but after AIT, the mean levels of beyond than only bringing a change in the molecular signature. Various
ICS decreased to 232 ± 87.23ug/mL. The decrease in mean ICS was long duration follow up studies have shown that AIT affects pulmonary
statistically significant (P = 0.001). The discontinuation rate in case of function variables. The present study was aimed at to assessing the effect
mild asthmatics taking ICS once a day was 43 % pre AIT to 26 % post AIT of AIT on PFT variables. It has been reported that AIT in conjugation
while in case of patient taking ICS twice day was 3.5 % pre AIT to 0% with pharmacotherapy is more effective than pharmacotherapy alone
post AIT Table 6 Fig 3. [26]. Sophia Tsabouri et al. and various others studies have reported a
higher safety profile of SLIT as compared to SCIT [12]. In our study, we
4. Discussion found that after one year of AIT, there was a marked change in certain
PFT variables. I. Djuric Filipovic et al. reported an increase in pre FEV1
This study evaluated the efficacy of SLIT in allergic asthmatics who % within one year of administration of SLIT. [27] We found that the pre
FEV1% was low during the baseline stage and it increased after
Table 3 administration of AIT. Similar findings were reported by Marogna et al.
Transitions in PFT variables of patients that underwent AIT. [28] The study by Kazutaka Mori et al. found that ICS do lead to in­
crease in pre FEV1% but discontuation of the same leads to deterioration
Variables Pre-AIT median ± S.D Post-AIT median ± S.D P-VALUE
of the pre FEV1 % within the time period of 12 weeks as compared to
FEV1/FVC(%) 81.88 ± 11.73 88.89 ± 12.70 0.022 this we found an sustained improvement in pre FEV11 % at the end of 48
FVC(L) 86.18 ± 19.08 87.87 ± 11.30 0.29
FEV1(L) 81.97 ± 17.8 87.76 ± 12.22 0.04
weeks supporting the notion that in our case of subjects the improve­
ment of pre FEV1% was largely due to the AIT. similar reports were
Wilkcons Rank sign Test.

39
A.H. Beigh et al.
found by Shengkun Zheng et al. in addition to decreased Pre FEV1% they
reported decrease in FEV1/FVC. [29,30] Although it has been shown by
wei du et al that there is improvement in Pre FEV1% by ICS but
concomitantly there is no improvement in Clinical Symptom score in our
study we found that with the improvement in pulmonary function var­
iable we also found an improvement in clinical symptom score. [31] A
study by Makoto Hoshino et al. also found an increase FEV1 post AIT,
however, the results were statistically insignificant. [32] The decreased
FEV1/FVC pre AIT was found to increase markedly post AIT. Our results
are supported by the study done by Hyo-In Rhyou et al, where they
compared AIT and non AIT groups. [33]Further, we did not find any
significant change in FVC in our patients. Similar results were reported
by Hoshino et al., Rosewich et al. &Cevit et al. [32,34]We evaluated the
serum levels of total IgE in our patients and found a decrease in total IgE
levels after allergen specific immunotherapy. The decrease in total IgE
after AIT has also been reported by Eman O. Arram et al. [9] Karakoc
et al. reports that ratio of Specific IgE to total IgE levels can predict
clinical improvement in patients sensitized to house dust mite treated
with immunotherapy. [35] We found a low Specific IgE to total IgE ratio
in pre AIT whereas the ratio increased post AIT. We did not found any
significance of Serum Specific HDM IgE levels with parameters studied.
The levels of serum Specific HDM IgE in pre AIT patients was found to be
low as compare to Post AIT same is found by Wenlong Liu et al. [36]
Increased numbers of eosinophils have been reported in the peripheral
blood of patients with eosinophilic disorders such as asthma. Eosino­
philic inflammation of the airways characterises disease severity in
subsets of individuals with severe asthma and there is a direct rela­
tionship between eosinophil count and the frequency of asthma exac­
erbations. However in our study, we found an insignificant decrease in
the eosinophill% count in our subjects. This observation can be as our
patients were with mild allergic asthma and there might not be exag­
gerated eosinophil counts in these patients. Most of the published
studies have considered clinical scores as the main efficacy parameter,
whilst immunological and inflammatory parameters have been only
occasionally investigated. In the present study, we assessed the severity
of asthma was by Allergy Control Questionnaire (ACQ). It was found the
after administration of AIT, the ACQ score decreased significantly. Our
observation is also supported by studies carried out by Djuric Filipovic
et al. & Karakoc-Aydiner E [27,13] wherein they reported sustained
clinical improvement of patients post AIT. ICS treatment is the basis of
asthma therapy in both children and adults because it targets the airway
inflammation. However, ICS treatment does not modify the disease
progression, and some patients fail to achieve adequate control. Our
study found a decrease in ICS usage post AIT. Similar results were re­
ported by Hyo-In Rhyou et al. We also found that with increase in the
time duration of AIT, there was a continuous decrease in dose of ICS.
[33]Above all, we found that the mean dosage of ICS significantly
decreased in pre AIT and post AIT scenario. Due to ethical issues, we
could not include pharmacotherapy controls in our study.
5. Conclusion
To conclude, our study strongly suggests that SLIT AIT is a safe and
important therapeutic intervention in selected cases of mild allergic
asthma patients as its benefit to risk ratio estimates are more inclined
towards the benefits rather than risks associated with pharmacotherapy.
Ethics approval and consent to participate
This study was approved by the institutional ethics committee (IEC)
SKIMS.
Consent for publication
Not applicable
40
Immunology Letters 230 (2021) 36–41
Availability of data and material
Please contact the author for data requests.
Funding
The study was funded by the institutional research fund.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgment
Not applicable.
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